6-oxygenated 16alpha, 17alpha-oxido-pregn-4-en-3, 20-diones and derivatives



No Drawing. Application November 21, 1958 i Serial No. 775,391

a claims. c1. 50-43955 1 The present invention relates to 6-oxygenated16a,17o

may be represented by the structural formula wherein Y is selected fromthe group consisting of carbonyl,. hydroxymethylene, and lower(alkanoyloxy)methylene radicals and Z is selected from the groupconsisting of methylene and carbonyl radicals. Lower- United StatesPatent Ofiice alkanoyloxy radicals which may be used are the acyloxy d 39? bqx c d s h a io m v. was mtiio qxy, ym m'isq vr xy, v lsry s y oxy,hexanoyloxy, heptanoyloxy, and octanoyloxy;

The 1611,17 e-oxido pregn-4-en-6B-ol-3,20-diones of the presentinvention are preparedby treating the appropriate 16a,l7a-oxido-pregn-4en-3,20rdione first with ethyl orthoformate to form the3-enol-ethy1ether then with alkaline hydrogen peroxide and isolating the product.The 6B-ols thus obtained can betreated with an oxidizing agent toyieldthe 6-oxo compounds of the present invention. Treatment of the 6/3-olswith an acid anhydride and isolation of tlie product affords theGp-alkanoyloxy de rivatives of the present invention.

Another compound of this invention, namely160:,17aoxido-5a-pregnane-3,6,20-trione, is obtained by treating16a,17a-oxido-pregn-4-en-6 8-ol-3,20-dione with an aqueous solution ofpotassium hydroxide in methanol and isolating the product.

Examples of suitable starting materials which may be used forpreparation of the compounds of this invention are16a,17a-oxido-pregn-4-en-3,ZO-dione and 160:,17aoxido-pregn-4-en-3,l1,20-trione.

As a specific example, treating 16a,17a-oxido-pregn-4- en-3,20-dionefirst with ethyl orthoformate in the presence of a catalytic amount ofp-toluenesulfonic acid, then with alkaline hydrogen peroxide andisolating the product afliords l6a,17a oxido-pregn 4 en 65 o1 3,20-dione. Treating the latter with chromic acid and isolating the productyields 16a,17a-oxido'pregn-4-en-3,6,20- trione, while treatment of the613-01 with acetic anhydride in the presence of pyridine and isolationof the product gives 6fl-acetoxy-16a,17a-oxido-pregn-4-en-3,ZO-dione.

The compounds of the present invention have valuable pharmacologicalproperties. They exhibit selective hormonal and anti-hormonalproperties, being, for example, effective in inhibiting the sodiumretention caused by desoxycorticosterone and its esters. They alsoexhibit estrogenic and progestational activity.

The invention will appear more fully from the examples which follow.These examples are set forth by temperature 205 2985 violet at 250millimicrons .with an. extinctioncoeflicient'of 45 2,907,759 e te Och ewe? way of illustration only and it will be understood that theinvention is not to be construed as limited in spirit or in scope by thedetails contained therein as many modifications in materials and methodswill be apparent in the disclosure to those "skilled in the art. Inthese examples temperatures are given in degrees centigrade C.).Quantities of materials are expressed in partsby weight and in parts byvolume which bear the same relation one to the other as kilograms toliters.

EXAMPLE 1 ;,1 7a-0x ido-pr egn-4-enodal-3,20-dione To a chilled solutionof 2 parts by weight of 160:,1704- oxido-pregn-4-en-3,20 dione in 10parts by volume of dioxane are added successively 2 parts by volume ofethyl orthoformate, 0.6'part by volume of a 10% 'solution ofp-toluenesulfonic acid in dioxane, and 0.1 part by volume of ethanol.The mixture is allowed to stand at room for 2 hours,t hen chilled and asolution of 02 part by weight of sodium hydroxid'ein 0.25 part by volumeof water and 6 parts by voluine of 30% hydro gen peroxide added. Themixture isallowed to stand at room temperature for 6 days after whichthe solid which precipitates is collected, washed with water, andrecrystallized from an acetone-methanol solution to -yield 166:",1711-It exhibits a maximum in the ultra-violet at 235.5 millimicrons withanextinction coefiicient $14,350."

EXAMPLE 2.

160a,]7a-oxido pregn-4 en-3,6,2O-trione To a suspension of 1.1 parts byweig t of 160:,17aoxid0-pregn-4-en-6}8ol-,2.0-dione in 25 parts byvolume of acetic acid is added a solution of 0.3 part by weight ofchromium trioxide in 15 parts by volume of acetic acid and 1 part byvolume of waters The mixture is stirred at roomtemperature for 3 hoursafter which it is diluted with methanol to destroy excess chromiumtrioxide and evaporated to dryness in vacuo. The residue is washed withwater and recrystallized from ether-petroleum ether solution to yield16a,17u-oxido-pregn-4-en-3,6,20-trione,

It exhibits a maximum in'the ultral0,5 00. In the infrared it exhibitsmaxima at 5.90, 5.95 and 6.27 microns.

EXAMPLE 3 opt-acetoxy] 6a,] 7 a-oxido-pregn-4-en-3,ZO-d ione ane). Itexhibits a maximum inthe ultra-violet at 235 millimicrons with anextinction coetficient of 13,350. In the infra-red it exhibits maxima at5.76, 5.90, 5.98, 6.18 and 8.02 microns.

By substituting an equivalent quantity of hexanoic anhydride andotherwise proceeding according to the herein described processes6/3-hexanoyloxy-l6a,17aoxido-pregn-4-en-3,20-dione is obtained. a

EXAMPLE 4 160a,] 7a-oxido-pregn-4-en-6p-01-3,] 1 ,ZO-irione To asuspension of 5.6 parts by weight ofl6a,170coxido-pregn-4-en-3,l1,20-trio11e in 20 parts by volume ofdioxane are added successively 6 parts by volume of ethyl orthoformate,1.8 parts by volume of a 10% solution of p-toluenesulfonic acid indioxane, and 0.3 part by volume of ethanol. The mixture is stirred atroom temperature for 2% hours then chilled and 0. 66 part by weight ofsodium hydroxide in 0.5 part by volume of water and 18 parts by volumeof30% hydrogen peroxide added. The mixture is allowed to stand at roomtemperature for 7 days. The precipitate which forms is collected, washedwith water, and chromatographed on silica gel, using 30% ethyl acetatein benzene as the eluant, to yield l6a,l7a-oxido-pregn-4 en 6501-3,11,20- trione which after recrystallization from acetone has a M.P.of 276-281". [a]1)=.+155 (0.94% in chloroform). It exhibits a maximum inthe ultra-violet at 231.5 millimicrons with an extinction coefficient of13,030.

EXAMPLE 1.60;,1 7a-oxid0-pregn-4-en-3,6,11,20-tetra0n2 To a stirredsolution of 2.7 parts by weight of 16LZ',17(Z'oxido-pregn-4-en-6f1-ol-3,11,20-trione in 8 parts by volume of aceticacid is added portionwise a solution of I 1 part by weight of chromiumtrioxide in 5 parts by volume of water and 50 parts by volume of aceticacid. The mixture is stirred at room temperature for 3 hours, thentreated with methanol to destroy unreacted chromium trioxide and pouredinto ice water.

with saturated sodium bicarbonate solution and evaporated to dryness invacuo. Trituration of the residue with ether followed by crystallizationfrom.ether-yields 16a,17a-oxido-pregn-4-en3,6,l1,20-tetraone, M.P. 206-210. It exhibits a maximum in the ultra-violet at 245-246 millimicronswith an extinction coeflicientof 11,130. Its-infra-red spectrum hasmaxima at 5.90, 5.95

' and 6.26 microns;

7 v EXAMPLE 6 V 6,5-a cetbxy-laJ 7ot-0xid0-pregn-4-en-i11 ,iZO-tribne Asolution of 1.91 parts by weight or 16a,-17a-oxido- .pregn-4en-63-ol-3,l1,20-trione in 30 parts by volume of acetic anhydride and 30parts by volume of pyridine is allowed to stand at room temperature for15 hours. Dilution with a large volume of water results in formation ofa. crystallineproduct which is collected by filtration and washed wellwith water. Recrystallization from ether affordsGB-acetoxy-16a,17a-oxido-pregn-4-en-3,11, 20-trione, M.P. 227-229". [a]=+148.5* (1% in The resulting .mixture is extracted withchloroform, theextract washed chloroform).

4 It exhibits a maximum in the ultra-violet at 230-231 millimicrons withan extinction coeflicient of 13,430. =Its infra-red spectrum has maximaat 5.80, 5.88, 5.90, 5.95, 6.18 and 8.05 microns.

By substituting an equivalent quantity of isobutyric anhydride andotherwise proceeding according to the herein described processes-63-isobutyroxy-16a,l7a-oxidopregn-4-en-3,11,20-trione is obtained.

EXAMPLE 7 16a,]7u-0xido-5oc-pregnane-3,6,20-tri0ne wherein Y is selectedfrom the group consisting of carbonyl, hydroxymethylene, andlower-(alkanoyloxy)- methylene radicals and Z is selected from the groupconsisting of methylene and carbonyl radicals.

16a,l7a-oxido-pregn-4-en-3,6,20-trione.

. 16cc, l7a-oxido-pregn-4-en-6B-ol-3 ,1l,20-trione.

. 16a,l7a-oxido-pregn-4-en-3,6,11,20-tetraone.

6;3-acetoxy-16u,l7a-oxido-pregn 4-ene3,1 l ,20-trione.

l 16a,17a-oxido-5a-pregnane-3,6,20-trione.

No references cited

1. A COMPOUND OF THE STRUCTURAL FORMULA